Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has one of the worst 1-year survival rates of any cancer. There is a major need for understanding of the molecular mechanisms leading to HCC. Identifying new tumor suppressor genes that regulate the development of HCC could lead to new treatments or prevention strategies for this unsolved public health problem. The central hypothesis is that PDK4 is a novel tumor suppressor gene for HCC. PDK4 is silenced in HCC and inactivation of PDK4 signaling modulates the metabolic fate of glucose to favor HCC development via crosstalk with both AMPK pathway and the NAD+-dependent deacetylase SIRT1 pathway. The hypothesis is supported by our preliminary results: 1) PDK4 is downregulated in human HCC; 2) The promoter of PDK4 gene is hypermethylated in human HCC cell line HepG2; 3) Overexpression of PDK4 decreases intracellular ATP pools and NAD+/NADH ratios; 4) Overexpression of PDK4 activates AMPK 2 and SIRT1 gene expression; 5) PDK4 suppresses HCC cell growth in vitro and inhibits Xenograft tumor growth in vivo; 6) PDK4 is hypermethylated in Shp-/- mouse livers that develop spontaneous HCC. PDK4 catalyzes the phosphorylation and inactivation of mitochondrial pyruvate dehydrogenase (PDH) which plays a central role in regulating glucose metabolism by producing Acetyl-CoA for oxidation in the Krebs cycle. Elucidating the function of PDK4 in the development of HCC will be the main focus of this application. We will test the hypothesis through two specific aims: 1) Characterize how PDK4 alters metabolic reprogramming in liver cancer cells; 2) Define the molecular mechanisms and physiological role of PDK4 in regulating HCC growth. Dr. Zhang has successfully completed 5 years post-doctoral training with a track record of productivity, and she is at the critical transiion point toward independence. Dr. Zhang has a strong background in nuclear receptor and molecular cancer research that will be further augmented by the described program in cancer metabolism. She will be guided by a well-matched mentoring committee of experts in relevant fields: Dr. Li Wang in nuclear receptors and lipid metabolism in liver cancer, Dr. Don Ayer in cancer cell glucose metabolism and Dr. Jared Rutter in mitochondrial metabolism. Additional career development advisors including Drs. E. Dale Abel, Curt Hagedorn, and Melinda Angus-Hill will provide objective reviews of her progress and ensure that her professional and scientific development activities are on track. The training in the career development plan will enable her to continue identifying challenging and relevant research questions and provide a collaborative working environment with experienced experts. This will facilitate the growth of an independent career in cancer biology with an emphasis on cancer metabolism.